Naturally occurring prostaglandins arc biologically active in a myriad of ways including hormone action, muscular contraction/relaxation, platelet aggregation/inhibition, intraocular pressure reduction and other cellular transduction mechanisms. Prostaglandins are enzymatically produced in nature from arachidonic acid. The arachidonic acid cascade is initiated by the prostaglandin synthase catalyzed cyclization of arachidonic acid to prostaglandin G.sub.2 and subsequent conversion to prostaglandin H.sub.2. Other naturally occurring prostaglandins are derivatives of prostaglandin H.sub.2. A number of different types of prostaglandins have been discovered including A, B, C, D, E, F and I-Series prostaglandins. These descriptions delineate substitution patterns of the various cyclopentane group central to all prostaglandins. Still other naturally occurring derivatives include thromboxane A2 and B2.
Due to their potent biological activity, prostaglandins have been studied for possible pharmaceutical benefit. However, due to potency of these molecules, as well as the ubiquitous presence of these agents and receptors and other biologically responsive tissue sites to their presence, numerous side effects have prevented the exploitation of the naturally occurring prostaglandins. It has also been difficult to pharmaceutically exploit the naturally occurring prostaglandins due to the relatively unstable nature of these molecules. As a result, researchers have been preparing and testing synthetic prostaglandin analogs, known as "prostanoids," for several decades.
In general, prostanoids can be described generically as consisting of (1) an alpha chain; (2) an omega chain; and (3) a cyclopentane group (or a heterocycle or other ring structure), as shown in formula (I). ##STR1##
In general, the R' groups of the ring structure are independently hydroxy, oxy, halogen and hydrogen groups. The omega chain has generally consisted of linear carbon backbones of varying lengths. The omega chains have also been of varying degrees of saturation, containing optional hetero-atoms and have terminated with a variety of alkyl and cycloalkyl groups. Alpha chains have consisted of numerous linear moieties and have involved various degrees of saturation. The alpha chains generally consist of a seven carbon chain and generally terminate with a carboxylic acid group or a variety of corresponding esters.
Another set of prostaglandins of particular interest are known as the "3-oxa-prostaglandins" or "3-oxa-prostanoids," which contain an oxygen atom at the three position, according to formula (II): ##STR2## wherein, R' is oxy, hydroxy, halogen, protected hydroxy or hydrogen; and the omega chain is generally five to twelve carbons in length with various substitutions including substitutions of hetero-atoms within the chain.
The compounds of formula (II) are typically synthesized by methods outlined in Scheme A, below, similar to methods disclosed in Buchmann et al., Tetrahedron Letters, volume 31, page 3425 (1990) and European Patent No. 0299914. ##STR3##
Generally, a lactone (1), wherein R' can be a hydroxy, halogen, protected hydroxy or hydrogen moiety and .omega. is an omega chain as generally known in the art, is converted to a hydroxy ester (2). The ester (2) is then silylated to give a protected hydroxy ester (3). Reduction of the protected hydroxy ester (3) yields a protected hydroxy aldehyde (4) and a side product alcohol (5). The protected hydroxy aldehyde (4) is then condensed with a trialkyl phosphonoacetate salt to give the unsaturated ester (6). Reduction of the ester (6) produces the allylic alcohol (7) which is then converted to the protected 3-oxa prostaglandin (8) by alkylation of the primary hydroxyl and the deprotected 3-oxa prostaglandin (9) by desilyation. The 3-oxa prostaglandin (9) can be further processed to yield a 9-keto or 9-halo analog and/or, to give an alpha chain terminating ester of choice.
The protected hydroxy aldehyde (4) is thus a key intermediate in the synthesis of 3-oxa prostanoids. The above synthetic route of Scheme A, however, is complicated by undesired side reactions which can result in poor yields, and the generation of substantial by-products. One problem is due to the reversible nature of the lactone ring opening reaction, i.e., (1) forming (2). The hydroxy ester (2) is unstable with respect to reclosure to lactone (1). In fact, in some cases the lactone (1) is preferred over the ester (2), causing poor yields of the protected hydroxy ester (3) and hence, poor yields of the protected aldehyde product (4). ##STR4##
Another problem with the above synthetic method is the formation of the by-product (5), the monoprotected diol. The unwanted by-product (5), which can result from uncontrolled reduction of (3), will not convert to the desired product (4) without further processing. Thus, low yields of (4) result in poor yields of the desired product. See for example, Cooper et al., Journal Of Organic Chemistry, volume 58, page 4280 (1993).
A need has arisen, therefore, to develop superior synthetic methods which allow the preparation of the various prostanoids of interest in greater yields.